Structural determinants of IgG1-FcγRIIIa interaction: a comprehensive computational study

Monoclonal antibodies (mAbs) have significantly transformed modern therapeutic strategies, with IgG1 representing the major subclass employed in clinical applications. Beyond antigen recognition, mAbs biological activity critically depends on Fc-mediated effector functions, which are triggered by interactions with immune receptors such as FcγRIIIa. Intrinsic structural determinants, including Fc N-glycosylation at Asn297 and light chain (LC) isotype, are known to modulate these interactions. However, their combined structural impact on the IgG1::FcγRIIIa complex remains incompletely characterized at the atomistic level. In this computational study, we employed chimeric homology modeling and molecular dynamics (MD) simulations to investigate how core fucosylation and LC isotype influence FcγRIIIa engagement. As representative case studies, two commercial IgG1 mAbs differing in LC composition (κ and λ) were selected, each modeled in both fucosylated and afucosylated states. Structural models of the corresponding mAb::FcγRIIIa complexes were generated and subjected to MD simulations to explore conformational stability, interface organization, and interaction impact over time. The simulations reveal that both glycosylation state and LC isotype significantly affect complex stability. Afucosylated antibodies and κ-LC variants display enhanced stabilization of the mAb::FcγRIIIa interface, whereas core fucosylation and the λ-LC isotype are associated with reduced complex stability. Overall, this study provides a comprehensive computational characterization of how Fc glycosylation and LC isotype cooperatively regulate IgG1 interaction with FcγRIIIa. By integrating structural modeling with conformational and energetic analyses, this work contributes to a more detailed understanding of the molecular determinants underlying Fc-mediated effector functions and supports the rational optimization of mAbs efficacy in therapeutic development.